Cellular proliferation and tissue remodeling are central to cellular responses to repair liver injury. Two lines of evidence suggest that the plasminogen system is critical for regulating liver repair: 1) Urokinase plasminogen activator (uPA) deficient hepatocytes exhibit delayed proliferation during liver regeneration. 2) CCl4 induced liver injury of plasminogen deficient mice leads to a severe defect in clearing pericentral necrotic hepatocytes resulting in fibrosis. Dr. Bezarra hypothesizes that the plasminogen system regulates liver repair via proteolytic clearance of abnormal hepatic matrix. The goal of Aim 1 is to define the role of plasminogen activation (urokinase or tissue-type) or interaction of uPA with its receptor in the control of liver repair. CCl4 liver injury experiments will be performed with plasminogen activator deficient mice (single or double mutants) or urokinase plasminogen activator receptor (uPAR) deficient mice. Repair of liver injury will be determined by cellular proliferation, removal of necrotic hepatocytes and remodeling of matrix architecture. Although increased hepatic expression of uPA in transgenic mice caused hepatocyte injury, the superimposed loss of plasminogen prevented development of liver injury and fibrosis. The second part of aim1 proposes to use partial hepatectomy and CCl4 injury on uPA transgenic/plasminogen deficient mice to determine whether urokinase has any regulatory role in liver repair independent of plasminogen. Plasminogen deficient mice with CCl4 induced liver injury exhibit poor removal of pericentral necrotic cells and excessive accumulation of hepatic matrix. In Aim 2, Dr. Bezerra proposes to use CCl4 liver injury with plasminogen deficient livers to test the hypothesis that plasminogen facilitates inflammatory cell influx and inhibits matrix production by stellate cells.